Total synthesis of haplomintrins A and B and studies on enantioselective quinone Diels-Alder reactions

单倍明特林A和B的全合成及对映选择性醌Diels-Alder反应的研究

• 批准号: 456623941
• 负责人: Dr. Stefan Wiesler
• 金额: --
• 依托单位: Department of Chemistry
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/456623941?language=en
• 关键词: Total; synthesis; haplomintrins; studies; enantioselective

The total synthesis of natural products (secondary metabolites) still remains an ongoing challenge and important part of organic chemistry, as natural products and their derivatives can often be used to identify new drugs or drug candidates. In order to accomplish the synthesis of mostly complex target frameworks, one typically relies on well-established reactions and methods. However, to tackle potential synthetic hardships or to circumvent a lack of existing approaches, new methods must be developed.One main class of plant secondary metabolites are terpenoids, some of which also possess significant biological activity. In 2015 Lou et al. reported two novel labdane-type diterpenoids, haplomintrins A and B, which they discovered from the Chinese liverwort Haplomitrium mnioides. The main objective of the present research proposal is to accomplish the first enantioselective total synthesis of haplomintrins A and B. In this vein, it is planned to carry out an enantioselective quinone Diels-Alder reaction as key step, using literature-known chiral catalysts. In addition, it should be tested whether a Nakada-type β-keto imide enables an improved chiral induction of copper bis(oxazoline) complexes, especially if the known chiral catalyst systems fail in this challenging quinone Diels-Alder reaction. With the Diels-Alder adduct in hand, a regio- and stereoselective addition of lithium furylacetylene to one of the carbonyl groups of the cis-decalin system is envisioned. The next step in the total synthesis of haplomitrin B is the transformation into the trans-decalin system, followed by cationic or radical deoxygenation and a subsequent alkynoic acid lactonization. Since one potential problem associated with the deoxygenation is the loss of stereo information at the propargylic position, it is also proposed to carry out the lactonization first. Then the deoxygenation of the structurally more rigid compound should not influence the stereo information. In order to prepare for further synthetic difficulties an alternative lactonization strategy is proposed involving a reduction of the propargyl group, followed by a hydroboration and lactonization of the resulting alcohol with the methylester. Finally, the last step toward haplomintrin B is a photoinduced [2+2] cycloaddition for which Lou et al. conducted some preliminary studies.With haplomintrin B in hand, a late-stage C–H functionalization by means of a Hartwig silylation should lead to haplomintrin A. Therefore, the carbonyl group of haplomintrin B should be stereoselectively converted to a hydroxy group using SmI2 as reducing agent. After subsequent silylation of the hydroxy group, the addition of RhCl(Xantphos) should provide the oxasilolane with the methyl group in δ-position. The subsequent Fleming-Tamao oxidation then leads to the δ-hydroxylated compound. Finally, a sequence of Swern oxidation, Pinnick oxidation and esterification should furnish haplomintrin A.

天然产物（次级代谢产物）的全合成仍然是有机化学的一个持续挑战和重要组成部分，因为天然产物及其衍生物通常可用于鉴定新药或候选药物。为了完成大部分复杂的目标框架的合成，通常依赖于成熟的反应和方法。然而，为了解决潜在的合成困难或克服现有方法的不足，必须开发新的方法。植物次生代谢产物的主要类别之一是萜类化合物，其中一些也具有重要的生物活性。2015年，Lou等人报道了两种新的劳丹型二萜类化合物，haplomintrin A和B，他们从中国苔类植物Haplomitrium mnioides中发现。本研究计划的主要目标是完成单核苷酸内含子A和B的首次对映选择性全合成。在这方面，计划使用文献已知的手性催化剂进行对映选择性醌Diels-Alder反应作为关键步骤。此外，应测试Nakada型β-酮酰亚胺是否能够改善铜双（恶唑啉）络合物的手性诱导，特别是如果已知的手性催化剂体系在这种具有挑战性的醌Diels-Alder反应中失败。与Diels-Alder加合物在手，区域和立体选择性加成锂呋喃乙炔的羰基之一的顺式-十氢化萘系统的设想。在全合成的单嘧酚B的下一步是转化成反式-十氢化萘系统，然后是阳离子或自由基脱氧和随后的炔酸内酯化。由于与脱氧相关的一个潜在问题是在炔丙基位置的立体信息的损失，因此还建议首先进行内酯化。那么结构上更刚性的化合物的脱氧不应影响立体信息。为了准备进一步的合成困难，提出了一种替代的内酯化策略，涉及炔丙基基团的还原，然后用甲酯对所得醇进行硼氢化和内酯化。最后，获得单倍内含子B的最后一步是光诱导的[2+2]环加成，Lou等人对此进行了一些初步研究。有了单倍内含子B，通过Hartwig甲硅烷基化的后期C-H官能化应该会产生单倍内含子A。因此，单核苷酸内含子B的羰基应立体选择性地转化为羟基使用Sm I 2作为还原剂。在随后的羟基的甲硅烷基化之后，RhCl（Xantphos）的添加应当提供在δ-位具有甲基的氧杂硅杂环戊烷。随后的Fleming-Tamao氧化反应生成δ-羟基化化合物。最后，Swern氧化、Pinnick氧化和酯化的顺序应提供haplomintrin A。